Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair

Abstract

During the menstrual cycle, the ovarian hormones oestradiol and progesterone control the ordered growth and differentiation of uterine cells. This remodelling process is critical for implantation of the developing embryo, the formation of the placenta, and maintenance of pregnancy. Failure of uterine tissues to respond appropriately to ovarian hormone signalling results in defective placentation, associated with a spectrum of pregnancy disorders such as recurrent miscarriages and preeclampsia. These obstetrical disorders are a major cause of maternal and perinatal morbidity and mortality. Progesterone exerts its action on target cells, at least in part, through binding to the progesterone receptor (PR), a member of the steroid/ thyroid hormone receptor superfamily of ligand-activated transcription factors. The mechanism by which progesterone controls the differentiation of human endometrial stromal cells, a process termed decidualization, in the secretory phase of the menstrual cycle is not well understood. Emerging evidence indicates that locally expressed factors and activation of the cAMP second messenger pathway integrate hormonal inputs and confer cellular specificity to progesterone action through the induction of diverse transcription factors capable of modulating PR function.

Hmgn1 acts downstream of C/EBPβ to regulate the decidualization of uterine stromal cells in mice

“…19,24 PKA inhibitor H89 could block the expression of Hmgn1 in the uterine stromal cells undergoing decidualization and the stimulation of cAMP on Hmgn1 expression. The siRNAmediated downregulation of Hmgn1 in the stromal cells could attenuate the effects of cAMP on the expression of differentiation markers Prl8a2 and Prl3c1, indicating that Hmgn1 is a critical regulator of cAMP-induced stromal differentiation during decidualization.…”

“…As a ubiquitous second messenger, cAMP prominently activates the PKA signal transduction pathway. 19 After stromal cells were pretreated with PKA inhibitor H89, 8-Br-cAMPinduced Hmgn1 expression was clearly dropped (Fig. 8B).…”

“…It has previously established that protein kinase A (PKA) signal transduction pathway is involved in the process of decidualization. 19 Thus we treated the uterine stromal cells with PKA inhibitor H89, then added estrogen and progesterone and monitored the expression of Hmgn1. The results found that H89 could evidently inhibit the expression of Hmgn1 in the uterine stromal cells undergoing decidualization (Fig.…”

“…Because cAMP is important for differentiation of uterine stromal cells into decidual cells, 19 we treated the stromal cells with cAMP analog 8-Bromoadenosine-cAMP (8-Br-cAMP, 500 mM). The results found that the expression of Hmgn1 was significantly elevated from 3 to 24 h after 8-Br-cAMP treatment (Fig.…”

Human endometrial milk fat globule-epidermal growth factor 8 (MFGE8) is up regulated by estradiol at the transcriptional level, and its secretion via microvesicles is stimulated by human chorionic gonadotropin (hCG)

“…Decidualization is the progressive remodeling of the endometrium that provides a receptive environment referred to as the "window of implantation" [6][7][8][9][10]. The gene expression profiles of the receptive endometrium have been characterized [11][12][13].…”